N-hydroxy protecting groups and process for the preparation of 3-acylamino-1-hydroxy-2-azetidinones

ABSTRACT

Processes for preparing the useful intermediates having the formula ##STR1## are disclosed herein, utilizing novel chemical compounds having the formula ##STR2##

This is a division of application Ser. No. 637,260, filed Aug. 3, 1984,now U.S. Pat. No. 4,581,170, issued Apr. 4, 1986.

RELATED APPLICATION

U.S. patent application Ser. No. 404,945, filed Aug. 4, 1982 discloses3-acylamino-2-oxoazetidin-1-yloxy acetic acids having antibacterialactivity.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 4,337,197, issued June 29, 1982, discloses asantibacterial agents, 3-acylamino-2-oxo-1-azetidinyl sulfates. Asintermediates for the preparation of these products, the referencediscloses, inter alia, compounds having the formula ##STR3## wherein X₁is acyl and X₂ and X₃ are hydrogen or organic substituents includingalkyl.

BRIEF DESCRIPTION OF THE INVENTION

This invention is directed to novel chemical compounds having theformula ##STR4## and to processes for using compounds of formula I andII to obtain compounds having the formula ##STR5##

The compounds of formula III are useful as intermediates for thepreparation of antibacterial agents; i.e.,3-acylamino-2-oxoazetidin-1-yloxy acetic acids, which are disclosed inU.S. patent application Ser. No. 404,945, filed Aug. 4, 1982, and3-acylamino-2-oxo-1-azetidinyl sulfates, as disclosed in U.S. Pat. No.4,337,197, issued June 29, 1982.

In formulas I, II and III, and throughout the specification, the symbolsare as defined below.

R₁ is an acyl group derived from a carboxylic acid; and

R₂ is hydrogen, lower alkyl or carbamoyloxymethyl.

The terms "lower alkyl" and "lower alkoxy", as used throughout thespecification, refer to alkyl groups having 1 to 4 carbon atoms.

The compounds of formula II can be converted to the correspondingcompound of formula III by simple treatment with a mild acid.

Alternatively, in those instances wherein R₁ is an acyl group derivedfrom a carboxylic acid that is also an amino protecting group removableunder neutral or basic conditions (referred to hereinafter as "A₁ "),the compounds of formula II can be converted to the correspondingcompound of formula III using the following reaction sequence: ##STR6##

The expression "an amino protecting group that is removable underneutral or basic conditions" refers to any group which will protect thenitrogen atom to which it is attached from reacting in the abovesequence, and which, at the end of the above-described reaction sequencecan be cleaved from the nitrogen atom at a pH equal to, or greater than,7.0. Exemplary of such groups are phenylmethoxycarbonyl and substitutedphenylmethoxycarbonyl (e.g., phenylmethoxycarbonyl substituted with4-methoxy, 4-chloro, 4-methyl, 2-methyl, 3-methyl, 2,4,6-trimethyl,3,5-dimethoxy, 2-nitro, or 4-nitro), allyloxycarbonyl,cinnamyloxycarbonyl, vinyloxycarbonyl, 1,1-dimethylpropynyloxycarbonyl,2-furanylmethyloxycarbonyl, 2-methylthioethyloxycarbonyl,2-trimethylsilylethyloxycarbonyl, 2-methylsulfonylethyloxycarbonyl,9-fluorenylmethyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl,2-cyanoethyloxycarbonyl, and 1,1-dimethyl-2-cyanoethyloxycarbonyl.

The term "acyl" refers to all organic radicals derived from an organicacid (i.e., a carboxylic acid) by removal of the hydroxyl group. Certainacyl groups are, of course, preferred but this preference should not beviewed as a limitation of the scope of this invention. Exemplary acylgroups are those acyl groups which have been used in the past to acylateβ-lactam antibiotics including 6-aminopenicillanic acid and derivativesand 7-aminocephalosporanic acid and derivatives; see, for example,Cephalosporins and Penicillins, edited by Flynn, Academic Press (1972),German Offenlegungsschrift No. 2,716,677, published Oct. 10, 1978,Belgian Pat. No. 867,994, published Dec. 11, 1978, U.S. Pat. No.4,152,432, issued May 1, 1979, U.S. Pat. No. 3,971,778, issued July 27,1976, U.S. Pat. No. 4,172,199, issued Oct. 23, 1979, and British Pat.No. 1,348,894, published Mar. 27, 1974. The portions of these referencesdescribing various acyl groups are incorporated herein by reference. Thefollowing list of acyl groups is presented to further exemplify the term" acyl"; it should not be regarded as limiting that term. Exemplary acylgroups are:

(a) Aliphatic groups having the formula ##STR7## wherein R_(a) is alkyl;cycloalkyl; alkoxy; alkenyl; cycloalkenyl; cyclohexadienyl; or alkyl oralkenyl substituted with one or more halogen, cyano, nitro, amino,mercapto, alkylthio, or cyanomethylthio groups.

(b) Carbocyclic aromatic groups having the formula ##STR8## wherein n is0, 1, 2 or 3; R_(b), R_(c), and R_(d) each is independently hydrogen,halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4carbon atoms, alkoxy of 1 to 4 carbon atoms or aminomethyl; and R_(e) isamino, hydroxyl, a carboxyl salt, protected carboxyl, formyloxy, a sulfosalt, a sulfoamino salt, azido, halogen, hydrazino, alkylhydrazino,phenylhydrazino, or [(alkylthio)thioxomethyl]thio.

Preferred carbocyclic aromatic acyl groups include those having theformula ##STR9## (R_(e) is preferably a carboxyl salt or sulfo salt) and##STR10## (R_(e) is preferably a carboxyl salt or sulfo salt).

(c) Heteroaromatic groups having the formula ##STR11## wherein n is 0,1, 2 or 3; R_(e) is as defined above; and R_(f) is a substituted orunsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1,2,3 or4 (preferably 1 or 2) nitrogen, oxygen and sulfur atoms. Exemplaryheterocyclic rings are thienyl, furyl, pyrrolyl, pyridinyl, pyrazolyl,pyrazinyl, thiazolyl, pyrimidinyl, thiadiazolyl and tetrazolyl.Exemplary substituents are halogen, hydroxyl, nitro, amino, protectedamino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1to 4 carbon atoms, or ##STR12##

Preferred heteroaromatic acyl groups include those groups of the aboveformulas wherein R_(f) is 2-amino-4-thiazolyl,2-amino-5-halo-4-thiazolyl, 4-aminopyrimidin-2-yl,5-amino-1,2,4-thiadiazol-3-yl, 2-thienyl, 2-furanyl, or6-aminopyridin-2-yl.

(d) [[(4-Substituted-2,3-dioxo-1-piperazinyl)carbonyl]amino]arylacetylgroups having the formula ##STR13## wherein R_(g) is an aromatic group(including carbocyclic aromatics such as those of the formula ##STR14##and heteroaromatics as included within the definition of R_(f)); andR_(h) is alkyl, substituted alkyl (wherein the alkyl group issubstituted with one or more halogen, cyano, nitro, amino or mercaptogroups), arylmethyleneamino (i.e., --N═CH--R_(g) wherein R_(g) is asdefined above), arylcarbonylamino (i.e., ##STR15## wherein R_(g) is asdefined above) or alkylcarbonylamino.

Preferred[[(4-substituted-2,3-dioxo-1-piperazinyl)carbonyl]amino]arylacetylgroups include those wherein R_(h) is ethyl, phenylmethyleneamino or2-furylmethyleneamino.

(e) (Substituted oxyimino)arylacetyl groups having the formula ##STR16##wherein R_(g) is as defined above and R_(i) is hydrogen, alkyl,cycloalkyl, alkylaminocarbonyl, arylaminocarbonyl (i.e., ##STR17##wherein R_(g) is as defined above) or substituted alkyl (wherein thealkyl group is substituted with one or more halogen, cyano, nitro,amino, mercapto, alkylthio, aromatic group (as defined by R_(g)),carboxyl (including salts thereof), amido, alkoxycarbonyl,phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl,dihydroxyphosphinyl, hydroxy(phenylmethoxy)phosphinyl, ordialkoxyphosphinyl substituents).

Preferred (substituted oxyimino)arylacetyl groups include those whereinR_(g) is 2-amino-4-thiazolyl. Also preferred are those groups whereinR_(i) is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl,2,2,2-trifluoroethyl or 1-carboxycyclopropyl.

(f) (Acylamino)arylacetyl groups having the formula ##STR18## whereinR_(g) is as defined above and R_(j) is ##STR19## amino, alkylamino,(cyanoalkyl)amino, amido, alkylamido, (cyanoalkyl)amido, ##STR20##

Preferred (acylamino)arylacetyl groups of the above formula includethose groups wherein R_(j) is amino or amido. Also preferred are thosegroups wherein R_(g) is phenyl or 2-thienyl.

(g) [[[3-Substituted-2-oxo-1-imidazolidinyl]carbonyl]amino]arylacetylgroups having the formula ##STR21## wherein R_(g) is as defined aboveand R_(k) is hydrogen, alkylsulfonyl, arylmethyleneamino (i.e.,--N═CH--R_(g) wherein R_(g) is as defined above), ##STR22## (whereinR_(m) is hydrogen, alkyl or halogen substituted alkyl), aromatic group(as defined by R_(g) above), alkyl or substituted alkyl (wherein thealkyl group is substituted with one or more halogen, cyano, nitro, aminoor mercapto groups).

Preferred[[3-substituted-2-oxo-1-imidazolidinyl]carbonylamino]arylacetyl groupsof the above formula include those wherein R_(g) is phenyl or 2-thienyl.Also preferred are those groups wherein R_(k) is hydrogen,methylsulfonyl, phenylmethyleneamino or 2-furylmethyleneamino.

DETAILED DESCRIPTION OF THE INVENTION

The novel chemical compounds of formula I, II and IV, and the processesof this invention, are useful for the preparation of the hydroxamates offormula III. These hydroxamates can be used to prepare3-acylamino-2-oxoazetidin-1-yloxy acetic acids and3-acylamino-2-oxo-1-azetidinyl sulfates. As described in U.S. patentapplication Ser. No. 404,945, filed Aug. 4, 1982 and U.S. Pat. No.4,337,197, issued June 29, 1982, these compounds are β-lactamantibiotics useful for combating bacterial infections (including urinarytract infections and respiratory infections) in mammalian species, suchas domesticated animals and humans.

The novel carboxy protecting group (derived from a compound of formulaI) used in compounds of formulas II, IV and V is extremely acid labile,and because of this, its removal from a compound of formula II or IV isa simple operation.

The compounds of formula I can be prepared by first reactingN-hydroxyphthalimide with a 2-(lower alkoxy)propene to yield a compoundhaving the formula ##STR23## The reaction is preferably run in thepresence of phosphorous oxychloride or pyridinium tosylate and anorganic amine such as triethylamine or pyridine.

Conversion of an N-hydroxyphthalimide derivative of formula VI to thecorresponding compound of formula I can be accomplished by treating thecompound with hydrazine or an alkylhydrazine.

The compounds of formula II and IV can be obtained by first reacting aprotected amino acid having the formula ##STR24## with a[(1-alkoxy-1-methyl)ethoxy]amine of formula I to yield the correspondingamide having the formula ##STR25## The reaction proceeds most readily ifthe protected amino acid of formula VII is first activated. Activatedforms of carboxylic acids are well known in the art and include acidhalides, acid anhydrides (including mixed acid anhydrides), activatedacid amides and activated acid esters. Mixed acid anhydrides for use inthe process of this invention can be formed from an amino acid offormula VII and a substituted phosphoric acid (such asdialkoxyphosphoric acid, dibenzyloxyphosphoric acid ordiphenoxyphosphoric acid), a substituted phosphinic acid (such asdiphenylphosphinic acid or dialkylphosphinic acid), dialkylphosphorousacid, sulfurous acid, thiosulfuric acid, sulfuric acid, a carboxylicacid such as 2,2-dimethylpropanoic acid, a carboxylic acid halide suchas 2,2-dimethylpropanoyl chloride, and others. Exemplary of theactivated amides which can be used in the process of this invention arethose formed from an amino acid of formula VII and imidiazole,4-substituted imidazoles, dimethylpyrazole, triazole, tetrazole ordimethylaminopyridine. Exemplary of the activated esters which can beused in the process of this invention are the cyanomethyl,methoxymethyl, dimethyliminomethyl, vinyl, propargyl, 4-nitrophenyl,2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, mesylphenyl,phenylazophenyl, phenylthio, 4-nitrophenylthio, p-cresylthio,carboxymethylthio, pyranyl, pyridinyl, piperidyl, and 8-quinolylthioesters. Additional examples of activated esters are esters with anN-hydroxy compound such as N,N-dimethylhydroxylamine,1-hydroxy-2(1H)pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, and1-hydroxy-6-chloro-1H-benzotriazole.

The amides of formula VIII which result from the coupling of an aminoacid of formula VII and a [(1-alkoxy-1-methyl)ethoxy]amine of formula Ican be cyclized by first converting the hydroxyl group to a leavinggroup, yielding a compound having the formula ##STR26## The conversionis accomplished by reacting a compound of formula VIII with a compoundhaving the formula

    A.sub.2 --SO.sub.2 --X                                     X

wherein X is chlorine or bromine and A₂ is alkyl, phenyl or substitutedphenyl (preferably methyl or p-methylphenyl). The reaction can be run inan organic solvent (e.g., pyridine or dichloromethane) in the presenceof an organic base (e.g., triethylamine).

Cyclization of a compound of formula IX to the corresponding2-azetidinone of formula IV can be accomplished by treating a compoundof formula IX with a base such as an alkali metal carbonate, bicarbonateor hydroxide; or a quaternary ammonium carbonate, bicarbonate, orhydroxide. The reaction is preferably carried out in water or a mixtureof water and an organic solvent.

Alternatively, the 2-azetidinones of formula IV can be prepared directlyfrom the corresponding compounds of formula VIII without firstconverting the hydroxyl group to a leaving group. Treatment of acompound of formula VIII with triphenylphosphine anddiethylazodicarboxylate yields a compound of formula IV.

Both of the methods disclosed above for ring closure of a compound offormula VIII result in the inversion of the stereochemistry of the R₂substituent.

Deprotection of the amino group of a compound of formula IV to obtainthe corresponding compound of formula V can be accomplished using knownprocedures that will depend on the particular protecting group (A₁)being removed. Treatment with hydrogen (using a catalyst such aspalladium) cleaves a phenylmethoxycarbonyl or substitutedphenymethoxycarbonyl protecting group.

Well known acylation techniques can be used to convert a compound offormula V to a compound of formula II. Exemplary techniques includereaction with a carboxylic acid (R₁ -OH) or corresponding carboxylicacid halide or carboxylic acid anhydride. The reactions with acarboxylic acid proceed most readily in the presence of a carbodiimidesuch as dicyclohexylcarbodiimide and a substance capable of forming areactive intermediate in situ such as N-hydroxybenzotriazole or4-dimethylaminopyridine. In those instances wherein the acyl group (R₁)contains reactive functionality (such as amino or carboxyl groups) itmay be necessary to first protect these functional groups, then carryout the acylation reaction, and finally deprotect the resulting product.

The [(1-alkoxy-1-methyl)ethoxy]amino protecting group can be readilycleaved from a compound of formula II or IV by treatment of the compoundwith acid.

Additional methodology for preparing the novel compounds of formulas IIand IV will be apparent to the practitioner of this invention. Forexample, a compound of formula IX can have its amino protecting group("A₁ ") cleaved and the resulting amino compound acylated prior tocyclization and cleavage of the [(1-alkoxy-1-methyl)ethoxy]aminoprotecting group. Still additional methodology comprises starting withan acylated amino acid having the formula ##STR27## reacting it with a[(1-alkoxy-1-methyl)ethoxy]-amine of formula I, cyclizing the resultingamide and the cleaving the [(1-alkoxy-1-methyl)ethoxy]-amino protectinggroup.

The following examples are specific embodiments of this invention.

EXAMPLE 1 [(1-Methoxy-1-methyl)ethoxy]amine (A)N-[1-Methoxy-1-methyl)ethoxy]phthalimide

N-Hydroxyphthalimide (40.7 g, 0.25 mol) was suspended in 160 ml of drytetrahydrofuran. 2-Methoxypropene (36 ml, 0.375 mol) was added followedby 1 drop of phosporous oxychloride. After 40 minutes, the solid haddissolved. Triethylamine (2 ml) was added and the tetrahydrofuran wasevaporated. The residue was taken up in 500 ml of ethyl acetate,filtered, washed with aqueous sodium bicarbonate and then saturatedaqueous sodium chloride, and dried over sodium sulfate. The solvent wasremoved and the white solid residue was dried under vacuum to afford53.6 g of the title compound.

(B) [(1-Methoxy-1-methyl)ethoxy]amine

N-[1-Methoxy-1-methyl)ethoxy]phthalimide (80.4 g, 0.342 mol) wasdissolved in 500 ml of dichloromethane. The mixture was cooled in anice/water bath and stirred mechanically. Methyl hydrazine (27.5 ml,0.513 mol) was added over 15 minutes. After an additional 15 minutes,the cold bath was removed and the mixture was stirred for 1 hour. Themixture was filtered, concentrated to a small volume, filtered again,and distilled under vacuum (60°-70° C., 20 mm of Hg) to afford 27.3 g ofthe title compound as a colorless liquid.

EXAMPLE 2[3S-[3α(Z),4β]]-3-[[(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-1-hydroxy-4-methyl-2-azetidinone(A) N²-[(Phenylmethoxy)carbonyl]-N-[(1-methoxy-1-methyl)ethoxy]-L-threoninamide

A solution of 171.5 g (0.677 mole) ofN-[(phenylmethoxy)carbonyl]-L-threonine, 68.7 g (0.679 mole) oftriethylamine and 6.8 g (0.086 mole) of pyridine in 1600 ml ofdichloromethane was coled to -20° C. and 82.0 g (0.680 mole) of pivaloylchloride was added dropwise. After stirring for 15 minutes, 85.3 g(0.812 mole) of [(1-methoxy-1-methyl)ethoxy]amine was added dropwise.After stirring for 30 minutes, the mixture was warmed to -15° C. and asolution of 101.7 g (1.211 mole) of sodium carbonate in 1 liter of waterwas added. The reaction mixture was allowed to warm to room temperatureand the organic layer was separated. The aqueous solution was extractedwith 400 ml of dichloromethane and the combined organic layers weredried with sodium sulfate. The solvent was concentrated to 400 ml and1.5 liters of ethyl acetate was added. The solution was concentrated to500 ml and after the addition of 50 ml of petroleum ether, the titlecompound started to crystallize. It was filtered off, washed withpetroleum ether and dried in vacuo, yielding 215.2 g of the titlecompound, melting point 88° C.

(B)(3S-trans)-3-[[(Phenylmethoxy)carbonyl]amino]-1-[(1-methoxy-1-methyl)ethoxy]-4-methyl-2-azetidinone

A solution of 20.4 g (60 mmole) of N²-[(phenylmethoxy)carbonyl]-N-[(1-methoxy-1-methyl)-ethoxy]-L-threoninamideand 6.1 g (60 mmole) of triethylamine in 200 ml of ethyl acetate wascooled to -2° C., and 6.9 g (60 mmole) of methanesulfonyl chloride wasadded dropwise. After stirring for one hour, the mixture was washed withice-cold water, sodium bicarbonate and brine. The solution was filteredover Hyflo, and 24 g (174 mmole) of potassium carbonate was added. Afterstirring overnight at ambient temperature, the potassium carbonate wasfiltered off, and the filtrate washed with ice-cold sodium bicarbonateand brine, dried with sodium sulfate and evaporated to dryness, yielding17.8 g of the title compound as a slightly yellow oil.

(C)[3S-[3α(Z),4β]]-3-[[(2-Amino-4-thiazolyl)-(methoxyimino)acetyl]amino]-1-[(1-methoxy-1-methyl)ethoxy]-4-methyl-2-azetidinone

(3S-trans)-3-[[(Phenylmethoxy)carbonyl]amino]-1-[(1-methoxy-1-methyl)ethoxy]-4-methyl-2-azetidinone(9.0 g, 27.9 mmole) was dissolved in 100 ml of dimethylformamide, and2.0 g of 10% palladium on charcoal was added. Hydrogen was bubbledthrough the mixture for one hour at ambient temperature and the catalystfiltered off. (Z)-2-Amino-4-thiazoleacetic acid (5.7 g, 27.9 mmole), 0.5g (3 mmole) of N-hydroxybenzotriazole and 6.3 g (30.6 mmole) ofdicyclohexylcarbodiimide were added to the filtrate and the resultingmixture was stirred for three hours at amibent temperature. The solventwas evaporated in vacuo and the residue was taken up in ethyl acetate.After washing with cold sodium bicarbonate and brine, the organic layerwas dried with sodium sulfate and evaporated in vacuo. The residue waspurified by column chromatography on silica gel using ethyl acetate assolvent, and yielding 4.0 g of the title compound, melting point 101°C., dec.

(D)[3S-[3α(Z),4β]]-3-[[(2-Amino-4-thiazolyl)-(methoxyimino)acetyl]amino]-1-hydroxy-4-methyl-2-azetidinone

[3S-[3α(Z),4β]]-3-[[(2-Amino-4-thiazolyl)-(methoxyimino)acetyl]amino]-1-[(1-methoxy-1-methyl)ethoxy]-4-methyl-2-azetidinone(0.53 g) was dissolved in 2 ml of methanol, and 10 ml of water wasadded. The pH was adjusted to 3.0 by adding 1N hydrochloric acid, andthe mixture was stirred for 10 minutes at room temperature. The methanolwas evaporated in vacuo, and the resulting aqueous solution freeze-driedyielding 0.43 g of the title compound, melting point 188° C., dec.

EXAMPLE 3(3S)-3-[[(Phenylmethoxy)carbonyl]amino]-1-hydroxy-2-azetidinone (A) N²-[(Phenylmethoxy)carbonyl]-N-[(1-methoxy-1-methyl)ethoxy]serinamide

N-[(Phenylmethoxy)carbonyl]serine (47.8 g, 0.2 mol) was dissolved in 440ml of dichloromethane by the addition of triethylamine (20.2 g, 0.2 mol)and pyridine (2 g, 0.025 mol). The mixture was cooled to -20° C. andpivaloyl chloride (24.2 g, 0.2 mol) was added dropwise within 20minutes. After 15 minutes, stirring at -20° C.,[(1-methoxy-1-methyl)ethoxy]amine (25.2 g, 0.24 mol) was added at -20°C. The mixture was stirred for 30 minutes at -20° C. and then added to asolution of sodium bicarbonate (30 g, 0.36 mol) in 300 ml of water. Thetemperature rose to 5° C. and the pH was greater than 7.2. After 15minutes, the organic layer was separated and the aqueous layer wasextracted with 50 ml of dichloromethane. The solvent was removed invacuo to a 50 ml volume, 400 ml of ethyl acetate was added and thesolvent was removed again to a 100 ml volume. Addition of some seeds wasfollowed by evaporating to a 50 ml volume. The resulting white crystalswere isolated by filtration and dried to afford 45.9 g of the titlecompound, melting point 96°-98° C.

(B) (3S)-3-[[(Phenylmethoxy)carbonyl] amino]-1-hydroxy-2-azetidinone

N² -[(Phenylmethoxy)carbonyl]-N-[(1-methoxy-1-methyl)ethoxy]serinamide(32.6 g, 0.1 mol) was suspended in 500 ml of ethyl acetate. Aftercooling to 0° to -5° C., triethylamine (13.1 g, 0.13 mol) was addedfollowed by dropwise addition of methanesulfonyl chloride (14.7 g, 0.12mol) within 15 minutes. The temperature did not exceed 0° C. After 1hour at 0° C. to -5° C., the reaction was complete.

Hydrazine hydrate (3.3 ml) was added and the mixture was stirred for 30minutes at 0° C. The mixture was washed with 200 ml of water, two 180 mlportions of aqueous monobasic sodium phosphate solution (100 g/l) and 80ml of brine. Potassium carbonate (40 g) was added to the solution ofmesylated material in ethyl acetate and the mixture was stirredovernight at 20° C. When the reaction had finished, it was filteredclear. Water (16 ml) and 21 ml of methanol were added to the solution.The mixture was acidified to pH 1 with 1N hydrochloric acid (ca. 25 ml),and about 40 ml of methanol was added to get a clear solution. Afterstirring for 4 hours at 20° C., the reaction had finished. The mixturewas washed twice with 100 ml of brine, then extracted with three 140 mlportions of aqueous potassium hydroxide (100 g/l) at 20° C. The aqueouslayer was acidified with conc. hydrochloric acid (ca. 50 ml) to get a pHof 2.3 and stirred for 30 minutes. The precipitate was filtered, washedwith water and dried at 40° C. to afford 17.2 g of the title compound,melting point 122°-123° C., dec.

EXAMPLE 4 (3S-cis)-3-[[(Phenylmethoxy)carbonyl]amino]-1-[(1-methoxy-1-methyl)ethoxy]-4-methyl-2-azetidinone(A) N²-[(Phenylmethoxy)carbonyl]-N-[(1-methoxy-1-methyl)ethoxy]allothreoninamide

Following the procedure of example 2A, but substituting allothreoninefor L-threonine, yielded the title compound.

(B)(3S-cis)-3-[[(Phenylmethoxy)carbonyl]amino]-1-[(1-methoxy-1-methyl)ethoxy]-4-methyl-2-azetidinone

N²-[(Phenylmethoxy)carbonyl]-N-[(1-methoxy-1-methyl)ethoxy]allothreoninamide(238.6 g, 0.731 mol) was suspended in 2.5 l of ethyl acetate. Aftercooling to -2° C., triethylamine (103.5 g, 1.022 mol) was added followedby the dropwise addition of methanesulfonyl chloride (117.2 g, 1.022mol). After 1 hour at 0° C., hydrazine hydrate (14.2 ml) was added andthe mixture was stirred for 45 minutes at 0° C. The mixture was washedwith water, aqueous monobasic sodium phosphate solution (100 g/l) andbrine.

Potassium carbonate (292.5 g) was added to the solution and the mixturewas stirred overnight at ambient temperature. After filtration, 290 mlof water and 370 ml of methanol were added, and the mixture was adjustedto pH 1 by adding 2N hydrochloric acid. After stirring for two hours atambient temperature, the mixture was washed with brine and water. Water(800 ml) was added and the pH was adjusted to 8.5 by the addition of anaqueous potassium hydroxide solution (100 g/l). The aqueous solution wasseparated and adjusted to pH 2.5 by the addition of concentratedhydrochloric acid. The precipitate was filtered off, washed with waterand dried in vacuo, yielding 95.2 g of the title compound, melting point133° C.

What is claimed is:
 1. A compound having the formula ##STR28##
 2. Thecompound in accordance with claim 1, [(1-methoxy-1-methyl)ethoxy]amine.